On December 5, 2016 Verastem, Inc. (NASDAQ:VSTM), focused on discovering and developing drugs to treat cancer, reported the presentation of results from the DYNAMO study, a Phase 2 clinical trial evaluating the safety and efficacy of duvelisib in patients with indolent non-Hodgkin lymphoma (iNHL) that is double refractory to both rituximab and chemotherapy, at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2016 Annual Meeting held December 3-6, 2016 in San Diego (Press release, Verastem, DEC 5, 2016, View Source;p=RssLanding&cat=news&id=2227733 [SID1234516975]). Duvelisib is an investigational, oral, dual inhibitor of phosphoinositide-3-kinase (PI3K)-delta and PI3K-gamma that has demonstrated clinical activity as a monotherapy in multiple hematologic cancers, including chronic lymphocytic leukemia (CLL), iNHL and T cell lymphomas.

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Results from the study were presented by Dr. Ian Flinn in an oral presentation, "DYNAMO: A phase 2 study demonstrating the clinical activity of duvelisib in patients with refractory indolent non-Hodgkin lymphoma." (Abstract number: 1218) Ian Flinn, M.D., Ph.D., Director of the Blood Cancer Research Program at Sarah Cannon Research Institute and the principal investigator on the DYNAMO study, described the results demonstrating duvelisib’s clinical activity in patients with double refractory iNHL, which included robust and durable responses, and a manageable safety profile.

The DYNAMO study included 129 evaluable patients with double refractory iNHL (median 3 prior anticancer regimens, range 1-18). The overall response rate (ORR) was 46% as determined by independent review committee (IRC; p=0.0001; 95% CI 0.37-0.55). Among disease subgroups, the ORR was 41% in follicular lymphoma (n=83), 68% in small lymphocytic lymphoma (n=28), and 33% in marginal zone lymphoma (n=18). Median duration of response (DOR) among all patients was 9.9 months. Notably, 83% of patients had reductions in the size of their target lymph nodes per IRC.

Duvelisib was generally well tolerated, with an expected and manageable safety profile with appropriate risk mitigation. The most common Grade ≥3 adverse events (occurring in ≥10% of patients) included neutropenia (28%), infection (18%), diarrhea (15%), thrombocytopenia (13%) and anemia (12%).

Dr. Flinn commented, "These results from the DYNAMO study presented at ASH (Free ASH Whitepaper) this year clearly show that duvelisib is clinically active with benefit observed across a variety of disease subtypes. It is important to recognize how heavily pre-treated the DYNAMO patients were, being refractory to both rituximab and chemotherapy. This patient population needs more treatment options."

"We are very encouraged by these results," said Gregory I. Berk, M.D., Chief Medical Officer of Verastem. "The activity and safety of duvelisib observed in the DYNAMO trial are just more evidence of the potential of this drug. We are committed to continuing duvelisib’s development with the belief that it may represent a valuable treatment for patients with very few treatment options."
A copy of the DYNAMO oral presentation is available here.

The following is a summary of other presentations at ASH (Free ASH Whitepaper) 2016:
Poster Presentations
Title: Preliminary results in first-line treatment of follicular lymphoma with the oral dual PI3K-delta,gamma inhibitor, duvelisib, in combination with rituximab or obinutuzumab
Lead Author: Carla Casulo, M.D., Assistant Professor, Wilmot Cancer Institute, University of Rochester
Abstract Number: 2979
Date and Time: Sunday, December 4, 2016, 6:00 – 8:00 pm PT
The poster can be viewed here.
Title: Inhibition of FAK Exerts Anti-Leukemic Activity and Potentiates ABT-199-Induced Apoptosis in AML
Lead Author: Bing Carter, Ph.D., Associate Professor, Department of Leukemia – Research, Division of Cancer Medicine, The University of Texas M.D. Anderson Cancer Center
Abstract Number: 1574
Date and Time: Saturday, December 3, 2016, 5:30 – 7:30 pm PT
The poster can be viewed here.

More About the Phase 2 DYNAMO Study
The DYNAMO study is a Phase 2, single-arm study which evaluated the efficacy and safety of duvelisib (25 mg twice daily) as a monotherapy in 129 patients with follicular lymphoma (n=83), small lymphocytic lymphoma (n=28) or marginal zone lymphoma (n=18) whose disease has progressed and who are refractory to rituximab and to either chemotherapy or radioimmunotherapy. The primary endpoint of the study was overall response rate as assessed by an independent review committee.

About the Tumor Microenvironment
The tumor microenvironment encompasses various cellular populations and extracellular matrices within the tumor or cancer niche that support cancer cell survival. This includes immunosuppressive cell populations such as regulatory T cells, myeloid-derived suppressor cells, M2 tumor-associated macrophages, as well as tumor-associated fibroblasts and extracellular matrix proteins which can hamper the entry and therapeutic benefit of cytotoxic immune cells and anti-cancer drugs. In addition to targeting the proliferative and survival signaling of cancer cells, Verastem’s compounds duvelisib and defactinib target the tumor microenvironment as a mechanism of action to potentially improve a patient’s response to therapy.

About Duvelisib
Duvelisib is an investigational, dual inhibitor of phosphoinositide 3-kinase (PI3K)-delta and PI3K-gamma, two enzymes that are known to help support the growth and survival of malignant B cells and T cells. PI3K signaling may lead to the proliferation of malignant B cells and is thought to play a role in the formation and maintenance of the supportive tumor microenvironment.1,2,3 Duvelisib is currently being evaluated in late- and mid-stage clinical trials, including DUO, a randomized, Phase 3 monotherapy study in patients with relapsed/refractory chronic lymphocytic leukemia (CLL)4, and DYNAMO, a single-arm, Phase 2 monotherapy study in patients with refractory indolent non-Hodgkin lymphoma (iNHL) that achieved its primary endpoint of overall response rate upon topline analysis of efficacy data5. Duvelisib is also being evaluated for the treatment of hematologic malignancies through investigator-sponsored studies, including T cell lymphoma.6 Information about duvelisib clinical trials can be found on www.clinicaltrials.gov.

About Defactinib
Defactinib (VS-6063) is an investigational inhibitor of Focal Adhesion Kinase (FAK), a non-receptor tyrosine kinase encoded by the PTK-2 gene that mediates oncogenic signaling in response to cellular adhesion and growth factors.7 Based on the multi-faceted roles of FAK, defactinib is used to treat cancer through modulation of the tumor microenvironment, enhancement of anti-tumor immunity, and reduction of cancer stem cells.8,9 Defactinib is currently being evaluated in three separate clinical collaborations in combination with immunotherapeutic agents for the treatment of several different cancer types including pancreatic, ovarian, non-small cell lung cancer, and mesothelioma. These studies are combination clinical trials with pembrolizumab and avelumab from Merck & Co. and Pfizer/Merck KGaA, respectively.10,11,12 Information about these and additional clinical trials evaluating the safety and efficacy of defactinib can be found on www.clinicaltrials.gov.

On December 5, 2016 TG Therapeutics, Inc. (NASDAQ:TGTX), reported the presentation of combination data from a Phase 1b study evaluating TGR-1202, the Company’s once-daily PI3K delta inhibitor, in combination with ibrutinib, the oral Bruton’s tyrosine kinase (BTK) (Press release, TG Therapeutics, DEC 5, 2016, View Source [SID1234516937]). This study is being run in collaboration with the Blood Cancer Research Partnership (BCRP) and Dana-Farber Cancer Institute (DFCI), Boston, MA. Data from this trial were presented today by the Principal Investigator, Matthew S. Davids, MD, of Dana-Farber Cancer Institute, during an oral session at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting in San Diego, CA.

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Michael S. Weiss, the Company’s Executive Chairman and Interim CEO commenting on the data said, "We and our investigators continue to be impressed with the ease of combining TGR-1202 with other novel agents. Here Dr. Davids demonstrated that the double blockade of the BCR pathway with dual oral once-daily inhibitors can be performed safely and conveniently, and derives high response rates in patients with both CLL and MCL. This all oral approach offers a unique and highly active alternative for patients who do not want to receive infused therapies but still want to advance their treatment beyond single agent ibrutinib, which may offer multiple benefits over single agent therapy. With one bone marrow confirmed complete response (CR) and 5 additional deep responses nearing radiographic CR out of the 17 evaluable CLL patients, we and our investigators believe we are seeing activity beyond what one might expect from either of these agents alone. We want to thank Dr. Davids and his collaborators at DFCI and the Leukemia & Lymphoma Society for providing support for this important investigator driven research and we look forward to follow-up data in the future from this study and data from our own triple therapy of TG-1101 plus TGR-1202 plus ibrutinib, which we are targeting for presentation next year."

The following summarizes the key highlights from this oral presentation which occurred today:

Oral Presentation: TGR-1202 in Combination with Ibrutinib in Patients with Relapsed or Refractory CLL or MCL: Preliminary Results of a Multicenter Phase I/Ib Study (Abstract Number 641)

This oral presentation includes data from patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL) treated with TGR-1202 in combination with Ibrutinib. 31 patients were evaluable for safety (18 CLL patients and 13 MCL patients), of which 28 patients were available for efficacy (17 CLL patients and 11 MCL patients.) CLL patients had a median of 1.5 prior lines of therapy (range 1-6), with 2 patients receiving prior ibrutinib and 4 receiving prior PI3K inhibitors. MCL patients had a median of 3 prior lines of therapy (range 2-5), with 2 patients also receiving prior ibrutinib.

Highlights from this oral presentation include:

88% (15 of 17) Overall Response Rate (ORR) (including Complete Response (CR), Partial Response (PR), and Partial Response with lymphocytosis (PR-L)) in patients with CLL, with 1 patient achieving a bone marrow confirmed CR and 5 patients with a > 80% nodal reduction, nearing radiographic CR
1 year progression free survival (PFS) and overall survival (OS) for CLL is 94% (n=17), with the longest patient on study approaching two years
73% (8/11) ORR in patients with MCL, with clinical benefit observed in two additional patients
1 year PFS and OS for MCL is 37% and 52%, respectively (n=11)
The combination appears well tolerated across all patients with no grade 3/4 transaminitis (liver toxicity), diarrhea, colitis or pneumonitis observed
PRESENTATION DETAILS:

The above referenced presentation is available on the Company’s website at www.tgtherapeutics.com, located on the Publications page.

On December 5, 2016 Apogenix, a biopharmaceutical company developing next-generation immuno-oncology therapeutics, reported that the final data from the Phase I clinical trial evaluating the safety and efficacy of asunercept (APG101) in lower (low and intermediate) risk patients with MDS were presented in an oral presentation at this year´s ASH (Free ASH Whitepaper) meeting on December 3, 2016 in San Diego, CA, USA (Press release, Apogenix, DEC 5, 2016, View Source [SID1234524575]).

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Asunercept is a fusion protein consisting of the extracellular domain of human CD95-receptor and the Fc domain of a human IgG1 antibody. Asunercept binds to the CD95-ligand on cells as well as to the soluble ligand, thus blocking the interaction between CD95-receptor and its cognate ligand. CD95-receptor is overexpressed on erythroid progenitor cells in the majority of patients with lower-risk MDS. Activation of CD95-receptor blocks erythrocyte production in the bone marrow. Its overexpression is a predictive factor of resistance to erythropoiesis stimulating agents (ESAs). In this Phase I study, all 20 patients enrolled were eligible for inclusion if they suffered from anemia resulting in a high transfusion burden, had hemoglobin levels of less than 10 g/dL, and were refractory to ESAs. Patients received once-weekly asunercept infusions for 12 weeks. Eight of the 20 patients (40%) showed a marked reduction of transfusion frequency for 6 months (end of observation period). Asunercept was generally well tolerated with no reported grade 3 or higher related adverse events. The most common treatment-emergent adverse events included peripheral edema (6 patients), urinary tract infection (4 patients), and oral herpes (3 patients).

"MDS patients display inappropriately increased CD95-receptor mediated signaling in the bone marrow, resulting in ineffective erythropoiesis," Prof W.K. Hofmann, head of the Department of Oncology & Hematology at the University Mannheim Heidelberg and study investigator, explained. "Asunercept inhibits this signaling pathway and promotes early-and late-stage erythroid differentiation, thereby correcting the ineffective erythropoiesis."

"Even though the study was only designed as a safety and pharmacodynamic Phase I trial, the results of short-term asunercept treatment in lower-risk MDS patients are very exciting," Harald Fricke, MD, Chief Medical Officer of Apogenix, said. "There is a substantial unmet medical need for patients who are refractory to treatment with ESAs and we look forward to continuing development of asunercept for this important indication."

Based on the effect of asunercept on early-and late-stage erythroid differentiation and the encouraging clinical activity in these patients, additional clinical Phase II studies are in preparation to test asunercept in lower-risk MDS patients with resistance to ESA treatment.

About Asunercept (APG101)
Apogenix’s lead immuno-oncology candidate asunercept is a fully human fusion protein that consists of the extracellular domain of the CD95-receptor and the Fc domain of an IgG1 antibody. Asunercept is being developed for the treatment of solid tumors and malignant hematological diseases. The World Health Organization (WHO) has recently assigned the international nonproprietary name (INN) "asunercept" for APG101.

On December 5, 2016 AbbVie (NYSE: ABBV), a global biopharmaceutical company, reported efficacy and safety findings from a Phase 2 study demonstrating that nearly half (48%) of patients with relapsed/refractory (R/R) marginal zone lymphoma (MZL) had a complete or partial response with single-agent ibrutinib (IMBRUVICA), as assessed by Independent Review Committee (IRC) investigators (Press release, AbbVie, DEC 5, 2016, View Source [SID1234516940]). The median duration of response was not reached.1 These data will be presented today in an oral presentation at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in San Diego, CA (abstract #1213). IMBRUVICA, a first-in-class Bruton’s tyrosine kinase (BTK) inhibitor, is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

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MZL is a diverse group of slow-growing non-Hodgkin’s lymphomas arising from white blood cells (lymphocytes) at the edges of lymphoid tissue.2 MZL accounts for approximately 12% of all cases of non-Hodgkin’s lymphoma in adults and the median age at diagnosis is 65 years old.3 There are currently no approved treatments or standards of care specifically indicated for patients with MZL in the United States.

"We are pleased with the 48% response rate seen with ibrutinib in this trial, as the hematology-oncology community has a need for effective new therapies to treat marginal zone lymphoma," said Ariela Noy, M.D., Hematologic Oncologist at Memorial Sloan Kettering Cancer Center in New York and lead investigator of the study.* "In particular, a non-chemotherapy targeted oral option like ibrutinib could represent an important step forward for patients with MZL to keep this incurable type of cancer under control."

In this multicenter, open-label trial, 63 MZL patients (including splenic MZL [SMZL], nodal MZL [NMZL] and extranodal MZL [EMZL] subtypes) received one or more prior therapies including at least one CD20-directed regimen (chemo-immunotherapy or rituximab monotherapy). In the study, 79% of patients experienced some tumor reduction (50 out of 63 patients) and overall response rates (ORR) was 48%, implying that BTK signaling is an important growth and survival factor in MZL. The median time to initial response was 4.5 months.1

Overall, the safety data from this study was consistent with the known safety profile of ibrutinib in B-cell malignancies. The most common adverse events (AEs) included fatigue (44%), diarrhea (43%), anemia (33%), nausea (25%), thrombocytopenia, peripheral edema and arthralgia (24% each), cough (22%), dyspnea and URTI (21% each). Grade 3 or 4 AEs occurred in 63% of patients. The most frequent were anemia (14%), pneumonia (8%) and fatigue (6%). Grade 1 and 2 atrial fibrillation occurred in four (6%) patients.1

"These findings contribute to the growing body of evidence exploring the use of ibrutinib in different types of hematologic cancers, including marginal zone lymphoma and its three sub-types," said Darrin Beaupre, M.D., Ph.D., Head of Early Development and Immunotherapy at Pharmacyclics LLC, an AbbVie company. "Results from this study support the recent submission of a supplemental New Drug Application to include more patients who may benefit from treatment with ibrutinib."

About the Study
The Phase 2 study evaluated the safety and efficacy of ibrutinib in patients with R/R MZL. The primary objective of the trial was ORR as assessed by an IRC. Duration of response (DOR), progression-free survival (PFS), overall survival (OS) and safety were secondary objectives.1 Data from this study were submitted to the U.S. Food and Drug Administration (FDA) in September 2016 as part of a supplemental New Drug Application (sNDA) to expand the current indication for IMBRUVICA.

About IMBRUVICA
IMBRUVICA is a first-in-class, oral, once-daily therapy that inhibits a protein called Bruton’s tyrosine kinase (BTK). BTK is a key signaling molecule in the B-cell receptor signaling complex that plays an important role in the survival and spread of malignant B cells.4,5 IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably.4

IMBRUVICA is approved to treat patients with CLL/SLL including patients with 17p deletion, patients with mantle cell lymphoma who have received at least one prior therapy and patients with Waldenström’s macroglobulinemia. Accelerated approval was granted for the MCL indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.4

IMBRUVICA was one of the first medicines to receive U.S. FDA approval via the new Breakthrough Therapy Designation pathway.

IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers and other serious illnesses. IMBRUVICA has one of the most robust clinical oncology development programs for a single molecule in the industry with nearly 30 (n=27) company-sponsored trials underway, 14 of which are Phase 3. In addition, there are more than 40 (n=44) investigator-sponsored trials taking place around the world. To date, more than 65,000 patients around the world have been treated with IMBRUVICA in clinical practice and clinical trials.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage – Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade 3 or higher bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA.

The mechanism for the bleeding events is not well understood. IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs of bleeding. Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre- and postsurgery depending upon the type of surgery and the risk of bleeding.

Infections – Fatal and nonfatal infections have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 14% to 29% of patients. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICA. Evaluate patients for fever and infections and treat appropriately.

Cytopenias – Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19% to 29%), thrombocytopenia (range, 5% to 17%), and anemia (range, 0% to 9%) based on laboratory measurements occurred in patients treated with single agent IMBRUVICA. Monitor complete blood counts monthly.

Atrial Fibrillation – Atrial fibrillation and atrial flutter (range, 6% to 9%) have occurred in patients treated with IMBRUVICA, particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (eg, palpitations, lightheadedness) or new-onset dyspnea should have an ECG performed. Atrial fibrillation should be managed appropriately and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines.

Hypertension – Hypertension (range, 6% to 17%) has occurred in patients treated with IMBRUVICA with a median time to onset of 4.6 months (range, 0.03 to 22 months). Monitor patients for new-onset hypertension or hypertension that is not adequately controlled after starting IMBRUVICA. Adjust existing antihypertensive medications and/or initiate antihypertensive treatment as appropriate.

Second Primary Malignancies – Other malignancies (range, 5% to 16%) including non-skin carcinomas (range, 1% to 4%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4% to 13%).

Tumor Lysis Syndrome – Tumor lysis syndrome has been infrequently reported with IMBRUVICA therapy. Assess the baseline risk (eg, high tumor burden) and take appropriate precautions. Monitor patients closely and treat as appropriate.

Embryo-Fetal Toxicity – Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA and for 1 month after cessation of therapy. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

ADVERSE REACTIONS

The most common adverse reactions (?20%) in patients with B-cell malignancies (MCL, CLL/SLL, and WM) were neutropenia** (64%), thrombocytopenia** (63%), diarrhea (43%), anemia** (41%), musculoskeletal pain (30%), rash (29%), nausea (29%), bruising (29%), fatigue (27%), hemorrhage (21%), and pyrexia (21%).

**Based on adverse reactions and/or laboratory measurements (noted as platelets, neutrophils, or hemoglobin decreased).

The most common Grade 3 or 4 non-hematologic adverse reactions (?5%) in MCL patients were pneumonia (7%), abdominal pain (5%), atrial fibrillation (5%), diarrhea (5%), fatigue (5%), and skin infections (5%).

Approximately 6% (CLL), 14% (MCL), and 11% (WM) of patients had a dose reduction due to adverse reactions.

Approximately 4%-10% (CLL), 9% (MCL), and 6% (WM) of patients discontinued due to adverse reactions. Most frequent adverse reactions leading to discontinuation were pneumonia, hemorrhage, atrial fibrillation, rash and neutropenia (1% each) in CLL patients and subdural hematoma (1.8%) in MCL patients.

DRUG INTERACTIONS

CYP3A Inhibitors – Avoid coadministration with strong and moderate CYP3A inhibitors. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose.

CYP3A Inducers – Avoid coadministration with strong CYP3A inducers.

SPECIFIC POPULATIONS

Hepatic Impairment – Avoid use in patients with moderate or severe baseline hepatic impairment. In patients with mild impairment, reduce IMBRUVICA dose.

Please see Full Prescribing Information: View Source

On December 5, 2016 Agios Pharmaceuticals, Inc. (Nasdaq:AGIO) reported new clinical data from the ongoing Phase 1 study evaluating single agent AG-120 in advanced hematologic malignancies at the 2016 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (ASH) (Free ASH Whitepaper) (Press release, Agios Pharmaceuticals, DEC 5, 2016, View Source;p=RssLanding&cat=news&id=2227727 [SID1234516941]). AG-120 is a first-in-class, oral, selective, potent inhibitor of mutant isocitrate dehydrogenase-1 (IDH1).

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As of August 1, 2016, data from the completed dose-escalation portion of the Phase 1 trial from 78 patients with advanced IDH1 mutant positive hematologic malignancies treated with AG-120, including 63 patients with relapsed and/or refractory (R/R) acute myeloid leukemia (AML), continue to show a favorable safety profile and durable clinical activity. Data from the ongoing expansion phases were not reported. For all dose escalation patients, an overall response rate of 38% (30 of 78) and a complete remission rate of 18% (14 of 78) were observed. For the 63 R/R AML patients, the overall response rate and complete remission rates were 33% (21 of 63) and 16% (10 of 63) respectively. Patients were on study treatment for up to 24.2 months with a median duration of response of 10.2 months for all responders and 6.5 months for the R/R AML responding patients.

In order to study the depth of response to single agent AG-120, molecular detection of the mutant IDH1 burden in blood and bone marrow samples (collected at pre-treatment and at least one on-treatment time point) were analyzed using next generation sequencing (NGS, FoundationOne Heme assay) in 67 patients from the dose-escalation portion of the study. Molecular clearance was defined as reduction of the IDH1 mutation below the limit of detection of the assay (1% for IDH). Molecular data show that treatment with AG-120 resulted in clearance of the IDH1 mutation in 36% of patients (5 of 14) in complete remission compared to 4% of patients (2 of 53) that did not achieve complete remission (p-value=0.003). This is the first demonstration that treatment with single agent AG-120 can result in mIDH1 clearance.

"AG-120 continues to demonstrate an impressive single-agent efficacy and safety profile in this cohort of high-risk relapsed or refractory AML patients, with some responses maintained for approximately two years," said Courtney DiNardo, M.D., lead investigator and assistant professor, department of leukemia at the University of Texas MD Anderson Cancer Center. "In addition, new molecular data for AG-120 suggests some patients experience clearance of the IDH1 mutant gene in their blood or bone marrow as assessed by next generation sequencing, demonstrating the depth of response that can occur with AG-120 therapy."

"We are encouraged by the durable clinical activity of AG-120 and are working to bring this medicine to waiting patients with IDH1 mutant positive AML whose disease has progressed after standard treatments," said Chris Bowden, M.D., chief medical officer of Agios. "We plan to explore a similar expedited regulatory strategy for AG-120 that is being utilized for enasidenib (AG-221), which could result in an NDA submission in 2017."

Updated Phase 1 Dose-Escalation Data for AG-120 in Advanced Hematologic Malignancies

Clinical and molecular data reported are from 78 patients treated with AG-120 in the dose escalation phase of the ongoing Phase 1; data from the ongoing expansions were not reported. Doses were administered from 200 mg to 1,200 mg total daily doses. As of August 1, 2016, seven patients (9%) remain on treatment. The median age of these patients is 68 (ranging from 36-89). Patients received a median of two prior chemotherapy regimens (ranging from zero to five). A safety and efficacy analysis was conducted for all 78 treated dose-escalation patients. In addition, longitudinal mutant IDH1 (mIDH1) variant allele frequency (VAF) data were available for 67 patients.

Safety Data

A safety analysis conducted for all 78 treated patients as of the data cut-off shows that AG-120 continues to demonstrate a favorable safety profile.

The majority of adverse events reported by investigators were mild to moderate, with the most common regardless of causality being fatigue, nausea, diarrhea, pyrexia and peripheral edema.
Fifty-three patients experienced at least one serious adverse event (SAE), the majority being disease related.
The maximum tolerated dose was not reached. The recommended Phase 2 dose was 500 mg once daily, which is being studied in the ongoing expansion phase of the trial.
Nine patients discontinued from the study due to death, including one reported as possibly related to AG-120.
All cause mortality at 30 and 60 days were 12% and 21%, respectively.
Efficacy Data

Thirty out of 78 treated patients achieved investigator-assessed objective responses for an overall response rate of 38%.

Of the 30 patients who achieved an objective response, there were 14 (18%) complete remissions (CR), eight CRs with incomplete neutrophil recovery or platelet recovery (CRi/CRp), six marrow CR (mCR)/morphologic leukemia-free state (MLFS) and two partial remissions (PR).
Of the 63 patients with R/R AML, 21 (33%) achieved an objective response, including 10 (16%) CRs, eight CRi/CRp, two MLFS and one PR.
Responses were durable, with a median response duration of 10.2 months (3.7- not estimable (NE)) overall and 6.5 months (3.7-NE) in the subset of patients with R/R AML.
Median duration of treatment is 3.2 months (ranging from 0.1 to 24.2 months).
IDH1 Mutational Clearance

Longitudinal mIDH1 VAF data were reported for 67 patients. Patients with IDH1 mutational clearance (IDH1-MC) were defined as having:

mIDH1 detected at screening (any sample type), and
no reported mIDH1 mutation in at least one on-study time point (FoundationOne Heme sensitivity of 1%).
Importantly, IDH1-MC was observed in 36% of CRs (5 of 14) and 4% of non-CRs (2 of 53). IDH1-MC was enriched in patients achieving CR (p-value = .003). The median time to mutational clearance was 2.7 months (ranging from 1.1 to 3.8 months). This is the first demonstration that treatment with single agent AG-120 can result in mIDH1 clearance. Agios is continuing to study the potential relationship between IDH1-MC and clinical benefit for patients with AML.

About the Ongoing Phase 1 Trial for AG-120 in Advanced Hematologic Malignancies
AG-120 is being evaluated in an ongoing Phase 1 trial that includes a dose-escalation phase and four expansion arms, including:

Arm 1: 125 IDH1 mutant positive AML patients who relapsed after bone marrow transplantation, are in second or later relapse, refractory to initial induction or reinduction treatment, or who relapse within one year of initial treatment, excluding patients with favorable-risk status
Arm 2: 25 untreated IDH1 mutant positive AML patients who are not candidates for standard-of-care chemotherapy
Arm 3: 25 patients with other non-AML IDH1 mutant, relapsed or refractory advanced hematologic malignancies
Arm 4: 25 patients with relapsed IDH1 mutant positive AML not eligible for arm 1 who have failed or are unable to receive standard of care
About Variant Allele Frequency (VAF)
Sequencing studies have demonstrated that most tumors exhibit extensive intra-tumor genetic heterogeneity characterized by individual cells that have different somatic mutations. For single-nucleotide mutations, or variants, the VAF is defined as the fraction of DNA sequence reads covering the variant position that contains the variant allele. This technique makes it possible to infer the subpopulations of tumor cells by counting the number of DNA sequence reads that contain a specific somatic mutation.

About IDH Mutations and Cancer
IDH1 and IDH2 are two metabolic enzymes that are mutated in a wide range of hematologic and solid tumor malignancies. Normally, IDH enzymes help to break down nutrients and generate energy for cells. When mutated, IDH increases production of an oncometabolite 2-hydroxyglutarate (2HG) that alters the cells’ epigenetic programming, thereby promoting cancer. 2HG has been found to be elevated in several tumor types. Agios believes that inhibition of the mutated IDH proteins may lead to clinical benefit for the subset of cancer patients whose tumors carry them.

About Acute Myelogenous Leukemia (AML)
AML, a cancer of blood and bone marrow characterized by rapid disease progression, is the most common acute leukemia affecting adults. Immature white blood cells known as myeloblasts, or "blasts" proliferate in the bone marrow rather than mature into normal blood cells. The decrease in normal blood cells can result in severe complications for patients including infections and dependence on blood product transfusions. AML incidence significantly increases with age, and according to the American Cancer Society, the median age of onset is 66. Less than 10 percent of U.S. AML patients are eligible for bone marrow transplant and the vast majority of patients do not respond to chemotherapy and progress to relapsed/refractory AML. The five-year survival rate for AML is approximately 20 to 25 percent. IDH1 and IDH2 mutations are present in about 15 to 23 percent of AML cases.